CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity

摘要

Obesityactivatesbothinnateandadaptiveimmuneresponsesinadiposetissue,butthemechanismscriticalforregulatingtheseresponsesremainunknown.CD40/CD40Lsignalingprovidesbidirectionalcostimulatorysignalsbetweenantigen‐presentingcellsandCD4+Tcells,andCD40Lexpressionisincreasedinobesehumans.Therefore,weexaminedthecontributionofCD40totheprogressionofobesity‐inducedinflammationinmice.CD40washighlyexpressedonadiposetissuemacrophagesinmice,andCD40/CD40Lsignalingpromotedtheexpressionofantigen‐presentingcellmarkersinadiposetissuemacrophages.Whenfedahighfatdiet,Cd40‐deficientmicehadreducedaccumulationofconventionalCD4+Tcells(Tconv:CD3+CD4+Foxp3?)invisceralfatcomparedwithwild‐typemice.Bycontrast,thenumberofregulatoryCD4+Tcells(Treg:CD3+CD4+Foxp3+)inleanandobesefatwassimilarbetweenwild‐typeandknockoutmice.Adiposetissuemacrophagecontentandinflammatorygeneexpressioninfatdidnotdifferbetweenobesewild‐typeandknockoutmice;however,majorhistocompatibilitycomplexclassIIandCD86expressiononadiposetissuemacrophageswasreducedinvisceralfatfromknockoutmice.SimilarresultswereobservedinchimericmicewithhematopoieticCd40‐deficiency.Nonetheless,neitherwholebodynorhematopoieticdisruptionofCD40amelioratedobesity‐inducedinsulinresistanceinmice.Inhumanadiposetissue,CD40expressionwaspositivelycorrelatedwithCD80andCD86expressioninobesepatientswithtype2diabetes.ThesefindingsindicatethatCD40signalinginadiposetissuemacrophagesregulatesmajorhistocompatibilitycomplexclassIIandCD86expressiontocontroltheexpansionofCD4+Tcells;however,thisislargelydispensableforthedevelopmentofobesity‐inducedinflammationandinsulinresistanceinmice...